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Home , Candida (fungus), Candida albicans, Malassezia, Pathogenic fungus, Trichosporon

Review albicans at Host Barrier Sites: Pattern Recognition Receptors and Beyond

Marc Swidergall 1,2

1 Division of Infectious , Harbor-UCLA Medical Center, Torrance, CA 90502, USA; [email protected] 2 Institute for and Immunity, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA  Received: 10 March 2019; Accepted: 21 March 2019; Published: 25 March 2019 

Abstract: Over the last decades, fungal have emerged as a growing threat to health. Although the human body is at potential risk, various body sites host several commensal fungal , including . In healthy individuals, C. albicans colonizes different mucosal surfaces without causing harm, while under diverse circumstances the can proliferate and cause . In this context, the understanding of host–C. albicans interactions in health and during infection may lead to novel therapeutic approaches. Importantly, host cells express pattern recognition receptors (PRRs), which sense conserved fungal structures and orchestrate innate immune responses. Herein, important findings on the topic of the recognition of C. albicans at host barrier sites are discussed. This review briefly summarizes the importance and functions of myeloid PRRs, reviews the fungal recognition and biology of stromal cells, and highlights important C. albicans virulence attributes during site-specific proliferation and invasion.

Keywords: immunity; host–fungus interaction; mucosal tissue

1. Introduction The human body is constantly threatened by the invasion of , and has evolved systems of immune tolerance to commensal microbiota as well as immune defense mechanisms to eliminate pathogens on and in the body. The mammalian is comprised of two branches: innate and adaptive immunity [1]. The is the first line of host defense against pathogens. Depending on the anatomic site of invasion, various epithelial cell linings orchestrate the innate response to eliminate proliferating microorganisms. The adaptive immunity is characterized by specificityand is involved in the elimination of pathogens in the late phase of infection, as well as in the generation of immunological memory. The incidence of fungal infections is rising, and presents a serious threat to public health [2]. Nevertheless, this risk is relatively underappreciated by the press, the public, and funding agencies [3]. Some fungal infections are highly lethal and disproportionately affect vulnerable patients, such as neonates, as well as transplant and cancer patients. Approximately 15% of health-care associated infections are caused by fungi [4]. Candida spp. account for 70–90% of all invasive fungal infections, and are a frequent cause of hospital-acquired systemic infections in the United States with crude mortality rates of up to 50% [4]. Among the Candida spp., C. albicans and C. glabrata rank first and second in isolation frequency, respectively [5]. However, C. albicans is the most common fungal in most clinical settings [6]. The morphological flexibility of C. albicans plays a crucial role in several aspects of infection and host recognition [7], while the pathogenicity of non-albicans spp. lacking hyphal formation, such as C. glabrata, is independent of morphology. C. albicans can cause two major types of infections in : superficial infections, such as , oral, or vaginal ,

Pathogens 2019, 8, 40; doi:10.3390/pathogens8010040 www.mdpi.com/journal/pathogens Pathogens 2019, 8, 40 2 of 14 and life-threatening systemic infections. While C. albicans resides on approximately 75% of mucosal surfaces in healthy individuals [8], its recognition is key to mount an antifungal response during fungal outgrowth in order to prevent disease. This review will provide current knowledge on the fungal recognition at barrier sites, with a focus on C. albicans.

2. Major “Classical” Fungal Pattern Recognition Receptors on Myeloid Cells Pattern recognition receptors (PRRs) recognize a variety of pathogen-associated molecular patterns (PAMPs) expressed by invading microorganisms [9–11]. PAMP–PRR interactions on myeloid cells induce downstream mechanisms designed to eliminate the pathogen, including phagocytosis, respiratory burst, and immune mediator release [12]. Various C- lectin-like receptors (CLRs), including Dectin-1, Dectin-2, and -inducible C-type lectin (Mincle), DC-Sign, and (MR), play major roles in antifungal immunity [13]. Dectin-1 recognizes exposed β-glucans in the cell wall of Candida, , and many other fungal species [14–16]. Ligand recognition activates the CARD9 pathway to trigger NF-κB activation, consequently inducing and chemokine production. In addition to inducting the secretion of and chemokines, Dectin-1 triggers phagocytosis and inflammasome activation in myeloid cells [17,18]. A homozygous polymorphism in Dectin-1 that eliminates expression on the cell surface confers increased susceptibility to recurrent vulvovaginal candidiasis (RVVC), but not oral mucosal infection [19]. The CLR Dectin-2, present on dendritic cells, , and , recognizes α-mannan [20]. Dectin-2-deficient mice are more susceptible to systemic candidiasis [21]. Fungal–Dectin-2 interactions activate CARD9, resulting in subsequent NF-κB activation. Dectin-3 recognizes α-mannans on the surfaces of C. albicans hyphae and induces NF-κB[22]. The CLR Mincle induces phagocytosis, fungal killing, and induction of TNF, IL-6, CXCL2, and KC in macrophages after fungal recognition [23]. Toll-like receptors (TLRs) are evolutionarily conserved transmembrane proteins that sense extracellular and intracellular pathogens in endosomes and lysosomes. TLR signaling activates either MyD88-dependent or TRIF-dependent pathways [24]. Various fungal species, as well as β-glucans, induce TLR2 or TLR2/TLR6-mediated cytokine responses [25]. TLR2 senses phospholipidomannan on the fungal surface [26]. Furthermore, TLR2 is able to directly bind chitin to trigger inflammation, dependent on the oligomer size [27]. On note, TLR2 is recruited to zymosan β-glucan-containing phagosomes and induces caspase-3/8-mediated apoptosis in in response to C. albicans, suggesting synergy between CLRs and TLRs [28–30]. Strikingly, TLR2 knockout mice are more resistant to disseminated Candida infection due to a decrease in the CD4+CD25+ regulatory T (Treg) cell population [31]. TLR4 senses O-linked mannosyl chains in the cell wall of C. albicans [32]. TLR4 knockout mice are more susceptible to systemic C. albicans infection due to reduced chemokine responses and impaired recruitment. However, cytokine responses are unaffected in TLR4 knockout macrophages [33]. Secreted C. albicans proteins are also able to bind and activate TLRs. A small secreted cysteine-rich protein secreted elicitor 1 (Sel1) can be sensed by both TLR2 and TLR4, leading to the activation of IKK/NF-κB and MAPK/AP-1 to trigger cytokine and TNFα production [34]. The intracellular receptor TLR9 recognizes unmethylated CpG DNA and is activated by fungal DNA to induce cytokine production in dendritic cells as well as phagosomal TLR9 recruitment in macrophages [35,36]. NOD-like receptors (NLRs) generally interact with apoptosis-associated speck-like protein containing a CARD (ASC) and procaspase-1 forming the inflammasome. In humans, polymorphisms in NLRs increase C. albicans colonization of the gut and NLRP3 polymorphism predisposes patients to RVVC [37]. In mice, macrophage-derived Nlrp3 recognizes C. albicans hyphae, and deficiency of ASC, NLRP3, and IL-1R1 leads to increased dissemination of mucosal C. albicans infection and mortality in vivo [38]. Additionally, stromal-cell-derived NLRC4 is critical for mediating immunity against [39]. RIG-I-like (RLR) receptors are DEAD box helicases and cytoplasmic pathogen recognition receptors that recognize and bind to nonself RNA to trigger innate immunity [40]. In macrophages, Pathogens 2019, 8, 40 3 of 14 the RLR MDA5 is specifically induced by C. albicans hyphae, and patients suffering from chronic mucocutaneous candidiasis (CMC) express lower levels of MDA5 than healthy controls [41]. Additionally, splenocytes from Mda5 knockout mice and human peripheral blood mononuclear cells (PBMCs) with different IFIH1 genotypes display an altered cytokine response to C. albicans. In addition to direct PRR interactions with fungal components myeloid receptor signaling is activated by host proteins bound to the fungal surface, including complement and antibodies [42]. Complement consists of approximately 30 fluid-phase and membrane-bound proteins that cooperate to form the cascade [43]. Following infection three different complement activation pathways commence rapidly to activate complement component 3 (C3) [44,45]. Opsonization with iC3b, a C3 fragment, is critical for fungal phagocytosis [46]. C3-deficient mice are more susceptible to infection with C. albicans due to impaired fungal clearance without affecting inflammatory responses [47]. The pentraxin family members PTX3 and serum amyloid P component (SAP) bind mannose-binding lectin (MBL) to trigger C1q recruitment resulting in enhanced C. albicans opsonophagocytosis by polymorphonuclear neutrophils (PMNs) [48]. In humans, polymorphisms in PTX3 are associated with the risk of Candida infection [49]. Elimination of immunoglobulin G (IgG)-opsonized C. albicans by neutrophils strictly depends on the Fcγ receptors, protein kinase C (PKC), and intracellular ROS accumulation, while non-opsonized C. albicans are recognized via complement receptor 3 (CR3; CD11b/CD18) inducing Syk and PI3K activation to clear phagocytosed C. albicans independent of ROS production [50]. Several PRRs, including Dectin-2, Dectin-3, and Mincle, associate with the FcγR signaling chain, which contains an immunoreceptor tyrosine-based activation motif (ITAM) to induce downstream signaling via Syk [22,51]. Cross-talk between myeloid PRRs, and within the corresponding innate immune pathways, enables the myeloid innate immune system to orchestrate immediate local and global responses [52,53]. Depending on different combinations of PAMPs, together with the order and dosage of sequential challenges, PRRs coordinate and amplify multiple pathways that are involved in antifungal responses and the regulation of cytokine synergy [54,55]. Along these lines, ITAM-coupled receptors cross-regulate signaling from heterologous receptors to fine-tune specific activation [56,57]. By contrast, certain cell types, such as natural killer (NK) cells, utilize specific PRRs to induce and amplify antifungal responses [58]. Thus, the broad repertoire of various PRRs on different myeloid cells ensures immediate recognition and antifungal mechanism during infection.

3. Barrier Sites in the Human Body The skin and mucosa define the frontier between the internal milieu and the external nonsterile environment [59]. These barriers are under intense scrutiny by the immune system and the maintenance of these barriers is paramount. Invading microorganisms and their products, such as secondary metabolites, remain a constant threat. Other cellular barriers, such as the blood–brain barrier (BBB), characterize protected distinct niches within the host. In addition to their physiological roles, these host barriers provide immune defense mechanisms against fungal infection, such as C. albicans [60,61].

3.1. Skin Immunity against C. albicans The skin surface is a unique niche, harboring a distinct community of bacteria and fungi [62,63]. In chronic mucocutaneous candidiasis (CMC) patients, C. albicans causes cutaneous lesions with the thickening, hyperkeratosis, and erythema of the skin [64,65]. In the skin, fungi interact primarily with keratinocytes, dendritic cells (DCs), and macrophages, as well as with myeloid cells that are recruited to the skin under inflammatory conditions [66,67]. The innate immune system and its effectors play a key role against cutaneous infections [68]. Fungal invasion of keratinocytes activates the expression of host defense (HDPs), antimicrobial molecules, which inhibit fungal proliferation [69–71]. In addition to producing HDPs, keratinocytes secrete chemokines and cytokines in response to invading C. albicans [72]. TLR2 expression and activation in fibroblasts is Pathogens 2019, 8, 40 4 of 14 required but not sufficient for protection against C. albicans invasion in a CD4+ T cell-supplemented model [73]. Furthermore, melanocytes play a key role in the innate immune response of the skin by recognizing C. albicans via TLR4, resulting in increased melanin content and inhibition of infection [74]. Melanization produces intermediate toxic compounds which exhibit strong antimicrobial activities. Additionally, melanin—the end-product—may have the capacity to trap, inhibit, and even kill invading pathogens [75]. Due to their location within stratified epithelia, Langerhans cells (LCs) are part of the first line of defense against pathogens present in the environment. Non-activated LCs are constantly migrating to the lymph nodes to present self-antigen and establish immune tolerance in homeostatic conditions [76]. On LCs Dectin-1 recognizes C. albicans , resulting in an IL-6-dependent Th17 response [77]. Recognition of C. albicans filaments by CD103+ dermal DCs (dDCs) through TLR-2 induces Th1 cell differentiation in the secondary lymphoid organs. Strikingly, these Th1 cells provide protection against a secondary systemic infection but not a secondary skin infection [77]. Additional recognition of invading fungi is provided by skin sensory neurons via the neuropeptide calcitonin-related product to direct IL-23–dependent γδ T cell IL-17 release, an integral cytokine of antifungal barrier immunity [78–81].

3.2. Oral Immunity in Response to C. albicans Recognition A multitude of antigens derived from food and the resident bacterial as well as fungal community continuously interact with oral epithelial cells. The oral cavity hosts up to 100 different fungal species [82], and the epithelial barrier is able to discriminate between commensal and pathogenic fungal forms [83]. Due to local or systemic immunosuppression, commensal fungi are able to proliferate resulting in oral disease. The most prevalent fungal-related oral disease is oropharyngeal candidiasis (OPC) which is caused mainly by C. albicans. Predisposing factors for oral C. albicans outgrowth include but are not limited to use of dentures, corticosteroid inhalers, cigarettes, broad-spectrum , and immunosuppressive and chemotherapeutic agents [84]. Patients with CMC are susceptible to debilitating, persistent, and refractory mucosal infections [85]. Mutations in STAT1, IL-23 and IL-12 receptors, IL-17RA, and IL-17F all lead to CMC [86]. Furthermore, patients with autosomal recessive autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) have mutations in the autoimmune regulator (AIRE) gene [87], resulting in a loss-of-function that causes the production of neutralizing autoantibodies against important cytokines with antifungal properties such as IL-17E, IL-17F, and IL-22 [88]. Autoantibodies against IL-22 and IL-17F are more common in APECED patients with CMC than in those without CMC, suggesting that type Th17 cytokines are central in human epithelial immunity against C. albicans infection [89,90]. However, recent experimental data have shown that autoantibodies against murine IL-17A do not increase susceptibility to OPC, while anti-IL-22 antibodies derived from patients increase the oral fungal burden [91]. C. albicans proliferation and the initiation of hyphal growth are required to induce a strong antifungal response in the oral cavity. While “classical” myeloid PRRs, such as TLR2 and Dectin-1, are expressed by human oral epithelial cells [92,93], these receptors are dispensable for the host defense against OPC in mice [94,95]. In human oral epithelial cells, Dectin-1 induces NF-κB signaling in response to proliferating C. albicans [93]. Furthermore, exposed β-glucan on the C. albicans surface is recognized by epithelial ephrin type A 2 receptor (EphA2) [93]. Fungal outgrowth in the oral cavity induces strong receptor activation and consequently downstream signaling through signal transducer and activator of transcription 3 (STAT3) and mitogen-activated protein kinases (MAPKs), which activate a distinct profile of chemokines, cytokines, and host defense peptides. During acute OPC, EphA2 knockout mice have a diminished antifungal cytokine and chemokine response in the tongue, resulting in higher oral fungal burden and a more severe disease [93]. Importantly, β-glucan (zymosan) or heat-inactivated C. albicans induce transient EphA2 signaling indicating that secondary fungal and/or host responses are required to mount a full antifungal response by oral epithelial cells. Therefore, this secondary messenger response might explain why the ingestion of fungal β-glucans does not induce an inflammatory response in the oral cavity. Pathogens 2019, 8, 40 5 of 14

C. albicans invades the epithelial cell lining of the oropharynx via distinct mechanisms. During fungal-induced endocytosis, C. albicans hyphae express invasins, which activate E-cadherin, the epidermal growth factor receptor (EGFR), and HER2 on the epithelial cell surface, resulting in internalization of the fungus [96,97]. During active penetration, C. albicans hyphae push their way into the epithelial cell [98]. Invasion of the oral epithelial cell lining results in tissue damage that is mainly caused by Candidalysin, a small toxin secreted by hyphal cells [99,100]. The damage of epithelial cells leads to IL-1 release, resulting in granulopoiesis and the expansion of innate CD4+ αβ T cell receptor (TCRαβ)+ cells [94,101]. TCRαβ+ cells, γδ T cells, and type-3 innate lymphoid cells (ILC3s) serve as IL-17 innate sources during acute OPC to amplify mucosal antifungal responses [102,103]. It is thought that the C. albicans morphology determines its pathogenicity in the oral cavity. However, a recent study shows that C. albicans strain variation modulates disease outcome in the oral cavity [104,105]. At the onset of oral infection the attenuation of inflammatory responses with a persistent/commensal C. albicans isolate is independent of Tregs and the immunoregulatory cytokine IL-10, and consequently independent of immunosuppression [104]. Strikingly, both pathogenic and commensal C. albicans strains induce conserved IL-17 signaling responses [105]. Importantly, C. albicans-induced epithelial damage correlates with a strong inflammatory response and rapid fungal clearance, while low epithelial cell damage is associated with oral colonization and fungal persistence [105]. However, lack of the damaging toxin Candidalysin does not abolish fungal clearance or C. albicans persistence in the immunocompetent host [94] suggesting that besides epithelial damage, other fungal factors, as well as host factors, contribute to pathogenicity during OPC and to fungal tolerance in homeostatic conditions.

3.3. C. albicans Recognition and Immunopathology during Vulvovaginal Candidiasis Vulvovaginal candidiasis (VVC) is a common mucosal infection, caused primarily by C. albicans. Worldwide, recurrent VVC affects about 138 million women annually (range 103–172 million), with 372 million women affected by recurrent episodes over their lifetime [106]. VVC is characterized by itching, burning, pain, redness of the vulva and vaginal mucosa, and discharge [107]. Neutrophils play an essential role during VVC immunopathology. In a mouse model of VVC depletion of these cells results in similar fungal burden but decreased histological evidence of vaginal inflammation [108] suggesting that symptoms are associated with PMN recruitment rather than fungal burden. Importantly, the yeast-to-hyphae transition is crucial to induce vaginal neutrophil immunopathogenesis. C. albicans recognition through epithelial TLR4 and specific intercellular adhesion molecule-3-grabbing nonintegrin-related 1 (SIGNR1) induces the expression of the alarmins S100A8/A9. These potent chemotactic factors recruit neutrophils to the site of infection [109]. Neutrophil recruitment is further amplified by Candidalysin-dependent epithelial damage [110]. Epithelial damage stimulates proinflammatory cytokine production, and consequently neutrophil recruitment [110]. In addition to innate phagocyte recruitment, neutrophil anergy contributes to chronic immunopathological state [111]. Vaginal heparan sulfate blocks the recognition of C. albicans Pra1 by neutrophils [112] consequently diminishing neutrophil activity and leading to PMN anergy [113].

3.4. Intestinal Immunity to C. albicans The lower gastrointestinal (GI) fungal community consists of Candida, Saccharomyces, Aspergillus, Cryptococcus, , Cladosporium, Galactomyces, and spp. [113]. Fungal dysbiosis, the alteration of the mycobiotic composition, results in altered local and systemic immunity through mechanisms that include the modulation of the cytokine milieu, the activation of different cell types and subsets, and the release of metabolites [114]. Intestinal epithelial cells, the mucus layer, HDPs, and IgA are crucial to maintain intestinal immunity [115,116]. IL-17/22-producing ILC3s and Th17 cells regulate defense and IgA expression [117,118]. In humans, intestinal inflammation expands C. albicans-specific and cross-reactive Th17 cells [119]. In otherwise immunocompetent mice, C. albicans GI colonization is independent of Th17 immunity [120]. In patients with Crohn’s disease, the presence of C. albicans and C. parapsilosis is increased in the inflamed mucosa [121]. In mice, fungal recognition by Pathogens 2019, 8, 40 6 of 14

CX3CR1-expressing mononuclear phagocytes predisposes intestinal inflammation [122]. Furthermore, in Crohn’s disease patients, a missense mutation in the gene encoding CX3CR1 is associated with impaired antifungal responses. C. albicans-driven IL-9 induction activates TGF-β in stromal mast cells (MCs) via the indoleamine 2,3-dioxygenase (IDO) enzyme, leading to intestinal immune tolerance, barrier permeability, inflammation, and dissemination [123]. In a mouse model of GI dissemination C. albicans translocation requires a combination of bacterial dysbiosis, fungal colonization, , and intestinal barrier dysfunction [124]. The hyphae-associated C. albicans invasin Als3 facilitates intestinal cell invasion [125]. Additionally, C. albicans-mediated necrotic epithelial damage mediates translocation through the intestinal barrier via a transcellular route [126].

3.5. Endothelial Recognition of and Immunity against C. albicans The dissemination of fungal starts with their entry into the bloodstream. C. albicans bloodstream infections arise from either transmigration of the fungus through the mucosal barrier of the GI tract or from biofilm formation on prosthetic material, such as intravenous catheters [127]. Kidneys are a primary target organ of C. albicans, and fungal invasion leads to loss of renal function and [128]. Exit from the circulation occurs by fungal adhesion to, and then penetration into, the endothelial lining of blood vessel. The interaction of C. albicans with the endothelial lining and blood vessel invasion involve a complex series of processes [129]. C. albicans hyphae bind to N-cadherin on the surface of endothelial cell, thus triggering endocytosis of the [130–132]. However, the role of N-cadherin and receptor-mediated endocytosis to induc antifungal responses in endothelial cells remains unknown. Endothelial cells express many “classical” PRRs, including TLR2, TLR3, TLR4, and TLR9 [133]. On endothelial cells, TLR3, NF-κB, and p38 MAPK pathways trigger proinflammatory gene expression in response to C. albicans invasion [134]. In vitro endothelial cells respond to infection with C. albicans by secreting TNFα, which stimulates CXCL8/IL-8 and E-selectin expression by an autocrine mechanism [135,136]. Depletion of MyD88 and IL-1R-associated kinase-1 (IRAK) diminishes C. albicans-induced NF-κB activation [134]. Furthermore, fungal-induced CXCL8/IL-8 expression is mediated by TLR3, rather than TLR2 and TLR4. Upregulation of vascular cell adhesion molecule 1 (VCAM-1) depends on membrane-bound TNFα and IL-1α/β, while intercellular adhesion molecule 1 (ICAM-1) expression is induced by a different mechanism. C. albicans-mediated chemokine expression critically depends on the NF-κB signaling pathway [135,136]. Thus, the production of leukocyte adhesion molecules and proinflammatory mediators by endothelial cells, is a crucial step to circumvent C. albicans dissemination after fungal recognition.

3.6. The Blood–Brain Barrier and C. albicans The blood–brain barrier (BBB) maintains the homeostasis of the central nervous system (CNS) microenvironment by restricting the access of macromolecules, cells, and pathogens. In forming the BBB, brain endothelial cells limit the diffusion of large or hydrophilic molecules into the central nervous system, while allowing the diffusion of small hydrophobic molecules [137]. Several studies in mice and humans have shown that C. albicans is able to cross the BBB [138–142]. Binding of C. albicans to human microvascular endothelial cells induces pseudopod-like structures and intracellular vacuole-like structures retaining C. albicans [143]. Fungal internalization occurs when the specific brain endothelial receptor heat shock protein 90kDa beta member 1 (gp96) binds to hyphal invasins [144]. In addition to invading the BBB by fungal-induced endocytosis, several microorganisms, including fungi, utilize a Trojan horse mechanism to invade the brain [145]. In this mechanism, phagocytes such as macrophages and monocytes phagocytose the fungus and carry it across the BBB and into the brain. Whether C. albicans utilizes a Trojan horse-like mechanism to invade the brain remains unclear. Microglia are the most frequent innate immune cells in the central nervous system. Upon C. albicans brain infection, microglia produce CXCL1 and CXCL2 in a CARD9-dependent Pathogens 2019, 8, 40 7 of 14 manner recruiting CXCR2+ neutrophils, which are required to control C. albicans proliferation in the brain [138,146].

4. Conclusions The field of antifungal barrier immunity has rapidly advanced in the past decade, marked by the dissection of barrier-specific immune responses in conjunction with human clinical data combined with knowledge from models of infection. The precise recognition of commensal and pathogenic C. albicans forms and the subsequent initiation of an antifungal network prevents fungal outgrowth in healthy individuals. The identification of novel host receptors, innate immune pathways, and fungal virulence attributes not only have important consequences for our understanding of the immune response to C. albicans, but they also open new avenues for future research. Moreover, several crucial questions related to barrier antifungal immunity remain unanswered. For example, which factors contribute to mucosal fungal tolerance in homeostatic conditions, and are mucosal persistent/commensal C. albicans isolates less virulent during systemic candidiasis? Additional fungal recognition receptors, antifungal pathway synergy, and the mechanism to initiate antifungal responses remain to be discovered, both in animal models and in human genetic studies.

Funding: Marc Swidergall was supported by the National Institute of Dental and Craniofacial Research of the National Institutes of Health under Award Number K99DE026856. The content is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health. Conflicts of Interest: The authors declare no conflict of interest.

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